Sleep typically occupies about one-third of a person's life and affects a person's mental and physical well being. It additionally affects mood, behavior and physiology. Sleep and the control of sleep is a complex process involving multiple chemicals and brain structures. It is a dynamic process involving distinct physiological changes and involves both positive and negative signaling. The regulation of sleep in humans is governed by three processes—each influenced by hormonal and environmental factors: a daily sleep-wake cycle influenced by a circadian rhythm (24 hour cycle) tied to light-dark cycles controlled by a cluster of about 10,000 neurons located in the hypothalamus behind the eyes, called the suprachiasmatic nuclei (Hastings M H. Central clocking. Trends Neurosci. 1997 October; 20(10):459-64.); a separable oscillating sleep homeostatic process influenced by prior sleep (Dijk D J, Lockley S W. Integration of human sleep-wake regulation and circadian rhythmicity. J Appl Physiol. 2002 February; 92(2):852-62.); and an ultradian rhythm which occurs within the 24 hour circadian cycle.
The need for sleep is a biological drive similar to thirst or hunger. Interestingly though, the function of sleep is largely unknown, however some evidence indicates that sleep is required for learning (Stickgold R, James L, Hobson J A. Visual discrimination learning requires sleep after training. Nat Neurosci. 2000 December; 3(12):1237-8; Gais S, Plihal W, Wagner U, Born J. Early sleep triggers memory for early visual discrimination skills. Nat Neurosci. 2000 December; 3(12):1335-9.). Additionally, sleep deprivation studies in rats have shown that when rats are not allowed to sleep, the end-result is death apparently related to immune system failure (Everson C A. Sustained sleep deprivation impairs host defense. Am J Physiol. 1993 November; 265(5 Pt 2):R1148-54.). In humans, similarly, mild sleep deprivation also results in indications of impaired immune system function (Irwin M, McClintick J, Costlow C, Fortner M, White J, Gillin J C. Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. FASEB J. 1996 April; 10(5):643-53.). Although specific sleep requirements vary from individual to individual, sleeping less than six hours per day has been shown to increase the risk of glucose intolerance and diabetes (Gottlieb D J, Punjabi N M, Newman A B, Resnick H E, Redline S, Baldwin C M, Nieto F J. Association of sleep time with diabetes mellitus and impaired glucose tolerance. Arch Intern Med. 2005 Apr. 25; 165(8):863-7.). Insomnia has been estimated to affect 40% of North Americans per year (Stoller M K. Economic effects of insomnia. Clin Ther. 1994 September-October; 16(5):873-97). A study by the U.S. National Sleep Foundation and the Gallup Organization involving 1,000 randomly selected Americans revealed that insomnia negatively impacts activities during waking function and effects quality of life (Roth T, Ancoli-Israel S. Daytime consequences and correlates of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. II. Sleep. 1999 May 1; 22 Suppl 2:S354-8.). Another study involving 261 insomnia sufferers and 101 individuals with no sleep complaints revealed that insomnia significantly impairs quality of life (Zammit G K, Weiner J, Damato N, Sillup G P, McMillan C A. Quality of life in people with insomnia. Sleep. 1999 May 1; 22 Suppl 2:S379-85.).
The neurotransmitter Gamma Aminobutyric Acid (GABA) is a primary inhibitory neurotransmitter. One of its effects is to induce sleep. The GABA-receptors are associated with chloride ion channels—signaling through the GABA-receptor changes the electrochemical gradient of the neuron, leading to activity inhibition (Olsen R W, Tobin A J. Molecular biology of GABAA receptors. FASEB J. 1990 March; 4(5):1469-80). Benzodiazepines are thought to act via interaction with the GABA receptor; enhancing the inhibitory effects of GABA. As such, Benzodiazepines are a widely used class of drugs primarily used as tranquilizers, muscle-relaxants, hypnotics or sedatives (Valenstein M, Taylor K K, Austin K, Kales H C, McCarthy J F, Blow F C. Benzodiazepine use among depressed patients treated in mental health settings. Am J Psychiatry. 2004 April; 161(4):654-61.). Additionally, Adenosine, a neuromodulator, may induce sleep by extracellular accumulation in specific brain regions such as the basal forebrain during prolonged wakefulness (Strecker R E, Morairty S, Thakkar M M, Porkka-Heiskanen T, Basheer R, Dauphin L J, Rainnie D G, Portas C M, Greene R W, McCarley R W. Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state. Behav Brain Res. 2000 November; 115(2):183-204; Zeitzer J M, Morales-Villagran A, Maidment N T, Behnke E J, Ackerson L C, Lopez-Rodriguez F, Fried I, Engel J Jr, Wilson C L. Extracellular adenosine in the human brain during sleep and sleep deprivation: an in vivo microdialysis study. Sleep. 2006 Apr. 1; 29(4):455-61.). Actions on both the GABA-benzodiazepine receptor complex (Mendelson W B. Sleep-inducing effects of adenosine microinjections into the medial preoptic area are blocked by flumazenil. Brain Res. 2000 Jan. 10; 852(2):479-81.) and/or the adenosine A1 receptor (Thakkar M M, Winston S, McCarley R W. A1 receptor and adenosinergic homeostatic regulation of sleep-wakefulness: effects of antisense to the A1 receptor in the cholinergic basal forebrain. J Neurosci. 2003 May 15; 23(10):4278-87.) can lead to the induction and maintenance of sleep. The stimulatory effects of caffeine are thought to be due to antagonism of adenosine A1 receptors (Sawynok J. Pharmacological rationale for the clinical use of caffeine. Drugs. 1995 January; 49(1):37-50.), wherein an aroused state is observed.
Another chemical associated with sleep is Melatonin. It is a hormone produced by the pineal gland from the amino acid tryptophan. Production is rhythmic in keeping with an intrinsic cycle of approximately 24-hours in duration, wherein levels are low during the day and increasing towards the nighttime (Wyatt J K, Ritz-De Cecco A, Czeisler C A, Dijk D J. Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day. Am J Physiol. 1999 October; 277(4 Pt 2):R1152-63). Melatonin appears to have two distinct effects on the circadian clock: neuronal inhibition and phase-shifting of the sleep cycle (Liu C, Weaver D R, Jin X, Shearman L P, Pieschl R L, Gribkoff V K, Reppert S M. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron. 1997 July; 19(1):91-102.). Oral administration of supplemental melatonin during the day induces sleepiness and improves night sleep (Dollins A B, Zhdanova I V, Wurtman R J, Lynch H J, Deng M H. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proc Natl Acad Sci USA. 1994 Mar. 1; 91(5):1824-8.). Two types of melatonin G-protein coupled receptors have been classified in mammals and termed MT1 and MT2 (Dubocovich M L, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005 July; 27(2): 101-10.).
Serotonin (5-hydroxytryptamine, 5HT), like melatonin, also displays a diurnal pattern; however, it functions in an opposing rhythm with daytime levels being higher than nighttime levels Portas C M, Bjorvatn B, Fagerland S, Gronli J, Mundal V, Sorensen E, Ursin R. On-line detection of extracellular levels of serotonin in dorsal raphe nucleus and frontal cortex over the sleep/wake cycle in the freely moving rat. Neuroscience. 1998 April; 83(3):807-1.). Three basic serotonin receptor types have been identified: 5HT-1, 5HT-2 and 5HT-3. Several subtypes of 5HT-1 have also been identified. The exact response of cells to serotonin depends on the receptor types expressed (Andrade R. of membrane excitability in the central nervous system by serotonin receptor subtypes. Ann N Y Acad Sci. 1998 Dec. 15; 861:190-203.) however, Serotonin has been shown to inhibit GABA receptors (Feng J, Cai X, Zhao J, Yan Z. Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J Neurosci. 2001 Sep. 1; 21(17):6502-11.), likely contributing to the opposing actions of serotonin and GABA and play a role in sleep.